The overall goal of this proposal is to elucidate the contributions of angiotensin II (A II) and endothelin (ET) to the progression of renal insufficiency. Rat models of chronic renal insufficiency will be used, and micropuncture, and morphologic and biochemical techniques will constitute the major methodologies employed. Four Specific Aims are enumerated to accomplish this objective. Specific Aim 1 will examine how the renin-angiotensin system contributes to hypertension and glomerular injury in renal insufficiency. The proposed studies will test the hypothesis that intrarenal AII activity is increased while circulating AII levels remain normal following renal ablation. Specific Aim 2 will identify the contribution of ET to altered glomerular function and structure in renal insufficiency. Specific Aim 3 will assess the interaction of AII mediated hypertension and local ET production in renal insufficiency. Initial studies will test the hypothesis that blood pressure reduction with an AII blocker reduces ET expression and thereby normalizes the hemodynamic actions of ET in remnant glomeruli. The fourth Specific Aim will assess the contribution of AII to tubulointerstitial injury. Recent studies suggest that AII promotes interstitial fibrosis independent of its effects on blood pressure and glomerular function. It is anticipated that with a better understanding of when and how AII contributes to the progression of renal disease, it will be feasible to more rationally prescribe AII antagonist therapy.